Malignant tumor therapy is progressing steadily in recent years by improving in successful rate for removal of the primary carcinoma by surgical operations, radiotherapies, or chemotherapies. However, even if a primary carcinoma is completely removed, death frequently occurs due to cancer metastasis.
In particular, melanoma, lung cancer, liver cancer, pancreatic cancer and other malignant tumors with a high malignancy, were difficult to detect in the early stages, so that by the time a malignant tumor is diagnosed, both the primary cancer and the metastatic cancer can be already existed simultaneously, and surgical treatment is impossible in many cases. Also, radiotherapies do not show good result for therapy of these malignant tumors. Moreover, most chemotherapeutic drugs in current clinical use, such as adriamycin, work by directly attacking the malignant tumor cells, but since they simultaneously target normal cells, they have strong side-effects which are a problem for clinical use. Therefore, no revolutionary new drug has emerged in decades. In order to overcome such a situation, it looks forward to the new type drugs for treating malignant tumors.
In this context, many basic studies and clinical studies have suggested a close relationship between malignant tumors and the blood coagulation and fibrinolysis systems, recently. For example, it is known that microcirculatory injury is caused by increased plasma fibrinogen levels, increased blood viscosity, abnormal blood rheology and other abnormalities of the blood coagulation and fibrinolysis systems in malignant tumor patients. It has also been reported that increased plasma fibrinogen levels or secretion of fibrinogen by the malignant tumor cells themselves causes the deposition of fibrinogen or fibrin into the extracellular matrix of the malignant tumor tissues, and these factors have the effect as part of the extracellular matrix to promote proliferation, invasion and metastasis of the malignant tumor cells (see for example Cancer Research 60:2033-2039 (2000); Ann. NY Acad. Sci. 936:406-425 (2001); and Blood 96:3302-3309 (2000)).
Focusing on the aforementioned relationship between malignant tumors and the blood coagulation and fibrinolysis systems, it has been confirmed that when malignant tumor cells are treated with fibrin in vitro, there is an increase effect of fibrin on the experimental metastasis of the malignant tumor cells into the lungs (see for example Clin. Exp. Metastasis 17:723-730 (1999)). Fibrin (also called Des AB fibrin or fibrin II) is a substance obtained when thrombin acts on fibrinogen, causing the release of fibrinopeptide A (FPA) and fibrinopeptide B (FPB) from the fibrinogen (see for example Nature 275:501-505 (1978) and Biochemistry 35:4417-4426 (1996)).
Moreover, focusing on the relationship between plasma fibrinogen concentrations and growth and metastasis of malignant tumors, it has been reported that administration of the thrombin-like enzymes batroxobin and ancrod, which have a defibrinogenating effect, reduces fibrinogen and inhibits malignant tumor growth and metastasis (see for example Eur. J. Cancer 16:919-923 (1980); and Acta Haematol. Jpn. 44:739-743 (1981)). Batroxobin, a thrombin-like serine protease produced from the venom of the snake Bothrops atrox moojeni, is a glycoprotein enzyme which releases only FPA from fibrinogen to produce Des A fibrin (also called fibrin I) (see for example Thromb. Haemost 36:9-13 (1976) and Thromb. Diath. Haemorrh. 45(Suppl.):63-68 (1971)).
Based on the assumption that fibrinogen functions as a barrier to protect malignant tumor cells from the attacks of the immune system, the technologies disclosed in above-mentioned references, attempted to inhibit growth and metastasis of malignant tumors by reducing fibrinogen levels with thrombin-like enzymes, thus making it easier for the immune system to attack the malignant tumor cells.
On the other hand, it is also known that the malignant tumor cell has characteristics of spreading and migration. “Spreading” of malignant tumor cells in this case, means that the round tumor cells form pseudopodia in response to some signal, and this is a biological behavior of tumor cells, which becomes the basis of tumor growth, invasion and metastasis.
Moreover, “migration” of malignant tumor cells means that the tumor cells move from their original locations through repeated bindings and dissociations between ligands and cell adhesion molecules in the cell membrane in response to some signal, and this is also a biological behavior which becomes the basis of tumor invasion and metastasis.
Therefore, by inhibiting the spreading and migration of malignant tumor cells, it is possible to inhibit tumor invasion and metastasis and thus inhibit malignant tumors.
However, there have been no reports on a preparation that can inhibit the spreading and migration of malignant tumor cells in order to effectively inhibit malignant tumor.
Furthermore, there have been no reports on the relationship between Des A fibrin (fibrinogen degradation product) and the spreading and migration of malignant tumor cells.